Myasthenia Gravis

Outline



Background



Anatomy



Pathophysiology



Epidemiology



Clinical Presentation



Work-up



Treatment



Rehabilitation

Background



Acquired autoimmune disorder



Clinically characterized by:



Weakness of skeletal muscles



Fatigability on exertion.



First clinical description in 1672 by
Thomas Willis

Anatomy



Neuromuscular Junction (NMJ)



Components:



Presynaptic membrane



Postsynaptic membrane



Synaptic cleft



Presynaptic membrane contains vesicles

with Acetylcholine (ACh) which are released

into synaptic cleft in a calcium dependent

manner



ACh attaches to ACh receptors (AChR) on

postsynaptic membrane

Anatomy



Neuromuscular Junction (NMJ)



The Acetylcholine receptor (AChR) is a
sodium channel that opens when bound by
ACh



There is a partial depolarization of the
postsynaptic membrane and this causes an
excitatory postsynaptic potential (EPSP)



If enough sodium channels open and a
threshold potential is reached, a muscle action
potential is generated in the postsynaptic
membrane

Pathophysiology



In MG, antibodies are directed toward
the acetylcholine receptor at the
neuromuscular junction of skeletal
muscles



Results in:



Decreased number of nicotinic acetylcholine
receptors at the motor end-plate



Reduced postsynaptic membrane folds



Widened synaptic cleft

Pathophysiology



Anti-AChR antibody is found in
80-90% of patients with MG



Proven with passive transfer
experiments



MG may be considered a B cell-
mediated disease



Antibodies

Pathophysiology



T-cell mediated immunity has some
influence



Thymic hyperplasia and thymomas are
recognized in myasthenic patients*

Epidemiology



Frequency



Annual incidence in US- 2/1,000,000 (E)



Worldwide prevalence 1/10,000 (D)



Mortality/morbidity



Recent decrease in mortality rate due to advances in

treatment



3-4% (as high as 30-40%)



Risk factors



Age > 40



Short history of disease



Thymoma



Sex



F-M (6:4)



Mean age of onset (M-42, F-28)



Incidence peaks- M- 6-7

th

decade F- 3

rd

decade

Clinical Presentation



Fluctuating weakness increased by exertion



Weakness increases during the day and
improves with rest



Extraocular muscle weakness



Ptosis is present initially in 50% of patients and
during the course of disease in 90% of patients



Head extension and flexion weakness



Weakness may be worse in proximal muscles

Clinical presentation



Progression of disease



Mild to more severe over weeks to months



Usually spreads from ocular to facial to bulbar to
truncal and limb muscles



Often, symptoms may remain limited to EOM and
eyelid muscles for years



The disease remains ocular in 16% of patients



Remissions



Spontaneous remissions rare



Most remissions with treatment occur within the
first three years

Clinical presentation



Basic physical exam findings



Muscle strength testing



Recognize patients who may develop
respiratory failure (i.e. difficult breathing)



Sensory examination and DTR’s are normal

Clinical presentation



Muscle strength



Facial muscle
weakness



Bulbar muscle
weakness



Limb muscle
weakness



Respiratory weakness



Ocular muscle
weakness

Clinical presentation



Facial muscle weakness is almost
always present



Ptosis and bilateral facial muscle
weakness



Sclera below limbus may be exposed
due to weak lower lids

Clinical presentation



Bulbar muscle weakness



Palatal muscles



“Nasal voice”, nasal regurgitation



Chewing may become difficult



Severe jaw weakness may cause jaw to hang

open



Swallowing may be difficult and aspiration may

occur with fluids—coughing and choking while

drinking



Neck muscles



Neck flexors affected more than extensors

Clinical presentation



Limb muscle weakness



Upper limbs more common than lower limbs

Upper Extremities

Deltoids
Wrist extensors
Finger extensors
Triceps > Biceps

Lower Extremities

Hip flexors (most common)
Quadriceps
Hamstrings
Foot dorsiflexors
Plantar flexors

Clinical presentation



Respiratory muscle weakness



Weakness of the intercostal muscles and the
diaghram may result in CO2 retention due to
hypoventilation



May cause a neuromuscular emergency



Weakness of pharyngeal muscles may collapse the
upper airway



Monitor negative inspiratory force, vital capacity
and tidal volume



Do NOT rely on pulse oximetry



Arterial blood oxygenation may be normal while CO2 is
retained

Clinical presentation



Occular muscle weakness



Asymmetric



Usually affects more than one extraocular

muscle and is not limited to muscles innervated

by one cranial nerve



Weakness of lateral and medial recti may

produce a pseudointernuclear opthalmoplegia



Limited adduction of one eye with nystagmus of the

abducting eye on attempted lateral gaze



Ptosis caused by eyelid weakness



Diplopia is very common

Clinical presentation



Co-existing autoimmune diseases



Hyperthyroidism



Occurs in 10-15% MG patients



Exopthalamos and tachycardia point to
hyperthyroidism



Weakness may not improve with treatment of MG
alone in patients with co-existing hyperthyroidism



Rheumatoid arthritis



Scleroderma



Lupus

Clinical presentation



Causes



Idiopathic



Penicillamine



AChR antibodies are found in 90% of patients
developing MG secondary to penicillamine
exposure



Drugs

Clinical presentation



Causes



Drugs



Antibiotics
(Aminoglycosides,
ciprofloxacin,
ampicillin,
erythromycin)



B-blocker
(propranolol)



Lithium



Magnesium



Procainamide



Verapamil



Quinidine



Chloroquine



Prednisone



Timolol



Anticholinergics

Differentials



Amyotropic Lateral

Sclerosis



Basilar Artery

Thrombosis



Brainstem gliomas



Cavernous sinus

syndromes



Dermatomyositis



Lambert-Eaton

Myasthenic

Syndrome



Multiple Sclerosis



Sarcoidosis and

Neuropathy



Thyroid disease



Botulism



Oculopharyngeal

muscular dystrophy



Brainstem

syndromes

Work-up



Lab studies



Anti-acetylcholine receptor antibody



Positive in 74%



80% in generalized myasthenia



50% of patients with pure ocular myasthenia



Anti-striated muscle



Present in 84% of patients with thymoma who
are younger than 40 years

Work-up



Lab studies



Interleukin-2 receptors



Increased in generalized and bulbar forms of
MG



Increase seems to correlate to progression of
disease

Work-up



Imaging studies



Chest x-ray



Plain anteroposterior and lateral views may
identify a thymoma as an anterior mediastinal
mass



Chest CT scan is mandatory to identify
thymoma



MRI of the brain and orbits may help to rule
out other causes of cranial nerve deficits
but should not be used routinely

Work-up



Electrodiagnostic studies



Repetitive nerve stimulation



Single fiber electromyography (SFEMG)



SFEMG is more sensitive than RNS in MG

Electrodiagnostic studies:

Repetitive Nerve Stimulation



Low frequency RNS (1-5Hz)



Locally available Ach becomes depleted at
all NMJs and less available for immediate
release



Results in smaller EPSP’s

Electrodiagnostic studies:

Repetitive Nerve Stimulation



Patients w/ MG



AchR’s are reduced and during RNS EPSP’s
may not reach threshold and no action
potential is generated



Results in a decremental decrease in the
compound muscle action potential



Any decrement over 10% is considered
abnormal



Should not test clincally normal muscle



Proximal muscles are better tested than
unaffected distal muscles

Repetitive nerve
stimulation



Most common employed stimulation

rate is 3Hz



Several factors can afect RNS results



Lower temperature increases the amplitude

of the compound muscle action potential



Many patients report clinically significant

improvement in cold temperatures



AChE inhibitors prior to testing may mask

the abnormalities and should be avoided for

atleast 1 day prior to testing

Electrodiagnostic studies:

Single-fiber electromyography



Concentric or monopolar
needle electrodes that
record single motor unit
potentials



Findings suggestive of NMF
transmission defect



Increased jitter and normal fiber
density



SFEMG can determine jitter



Variability of the interpotential
interval between two or more
single muscle fibers of the
same motor unit

Electrodiagnostic studies:

Single-fiber electromyography



Generalized MG



Abnormal extensor digiti minimi found in 87%



Examination of a second abnormal muscle will
increase sensitivity to 99%



Occular MG



Frontalis muscle is abnormal in almost 100%



More sensitive than EDC (60%)

Workup
Pharmacological testing



Edrophonium (Tensilon test)



Patients with MG have low numbers of AChR

at the NMJ



Ach released from the motor nerve terminal

is metabolized by Acetylcholine esterase



Edrophonium is a short acting Acetylcholine

Esterase Inhibitor that improves muscle

weakness



Evaluate weakness (i.e. ptosis and

opthalmoplegia) before and after

administration

Workup
Pharmacological testing

Before After

Workup
Pharmacological testing



Edrophonium (Tensilon test)



Steps



0.1ml of a 10 mg/ml edrophonium solution is
administered as a test



If no unwanted effects are noted (i.e. sinus
bradychardia), the remainder of the drug is
injected



Consider that Edrophonium can improve
weakness in diseases other than MG such as
ALS, poliomyelitis, and some peripheral
neuropathies

Treatment



AChE inhibitors



Immunomodulating therapies



Plasmapheresis



Thymectomy



Important in treatment, especially if
thymoma is present

Treatment



AChE inhibitor



Pyridostigmine bromide (Mestinon)



Starts working in 30-60 minutes and lasts 3-6
hours



Individualize dose



Adult dose:



60-960mg/d PO



2mg IV/IM q2-3h



Caution



Check for cholinergic crisis



Others: Neostigmine Bromide

Treatment



Immunomodulating therapies



Prednisone



Most commonly used corticosteroid in US



Significant improvement is often seen after a

decreased antibody titer which is usually 1-4 months



No single dose regimen is accepted



Some start low and go high



Others start high dose to achieve a quicker response



Clearance may be decreased by estrogens or

digoxin



Patients taking concurrent diuretics should be

monitored for hypokalemia

Treatment
Behavioral modifications



Diet



Patients may experience difficulty chewing and

swallowing due to oropharyngeal weakness



If dysphagia develops, liquids should be thickened



Thickened liquids decrease risk for aspiration



Activity



Patients should be advised to be as active as

possible but should rest frequently and avoid

sustained activity



Educate patients about fluctuating nature of

weakness and exercise induced fatigability

Complications of MG



Respiratory failure



Dysphagia



Complications secondary to drug
treatment



Long term steroid use



Osteoporosis, cataracts, hyperglycemia, HTN



Gastritis, peptic ulcer disease



Pneumocystis carinii

Prognosis



Untreated MG carries a mortality rate of
25-31%



Treated MG has a 4% mortalitiy rate



40% have ONLY occular symptoms



Only 16% of those with occular symptoms
at onset remain exclusively occular at the
end of 2 years

Rehabilitation



Strategies emphasize



Patient education



Timing activity



Providing adaptive equipment



Providing assistive devices



Exercise is not useful

References

1. Delisa, S. A., Goans, B., Rehabilitatoin Medicine Principles

and Practice, 1998, Lippencott-Raven

2. Kimura, J., Electrodiagnosis in Diseases of Nerve and

Muscle, F.A.Davis Company, Philadelphia

3. Rosenberg, R. N., Comprehensive Neurology, 1991,

Raven Press Ltd

4. O’sullivan, Schmidtz, Physical Medicine and Rehabilitation

Assessment and Treatment, pg. 151-152

5. Grabois, Garrison, Hart, Lehmke, Neuromuscular

Diseases, pgs. 1653-1655

6. Shah, A. K., www.emedicine.com, Myasthenia Gravis,

2002, Wayne State University

7. Tensilon test pictures

http://www.neuro.wustl.edu/neuromuscular/mtime/mgdx.

html

Thank you!

Questions, comments, or suggestions?